A new class of pain-relieving drugs, derived from histamine antagonists, has been discovered. The prototype (named improgan) shows the following characteristics after injection into the brain: A) highly effective attenuation of thermal and mechanical nociception in two rodent species, B) absence of impairment of motor function, C) independence from known opioid or histamine receptors, and D) lack of tolerance with daily dosing. The experiments below in rats and mice will reveal the mechanism of action of improgan, and evaluate the efficacy of this drug in clinically relevant pain models: (1) The improgan receptor has not yet been discovered. Radioligand binding studies with 3H-cimetidine will test the hypothesis that this ligand binds to the brain improgan receptor. Validation of this assay will lead to discovery of the improgan receptor, and to the development of new drugs acting on this receptor. (2) The effects of improgan on inflammatory and neuropathic nociceptive models will evaluate the efficacy of this drug in clinically relevant pain. (3) "Off-cells" in the rostral ventromedial medulla (RVM) are crucial for RVM-mediated analgesia, and improgan appears to activate these cells. Combinations of single unit recording, microinjections, behavioral testing and iontophoresis will beperformed to reveal the neurophysiological basisfor improgan antinociception. (4) Improgan antinociception is blocked by cannabinoid CBj antagonists, yet this drug lacks affinity for the CBi receptor. In vivo studies with cannabinoid drugs and anti-sense oligonucleotides will verify mechanistic rolesfor CBi receptors and endogenous cannabinoids (endocannabinoids) in improgan antinociception. These collaborative experiments between pharmacologists, neurophysiologists and chemists will discover the mechanism of action of this novel class of agents and lead to the development of new, non-opioid pharmacotherapies for pain.